Comparison of the Efficacy of Nicardipine, a New Calcium

Postgrad Med J: first published as 10.1136/pgmj.63.740.463 on 1 June 1987. Downloaded from

Postgraduate Medical Journal (1987) 63, 463-466

Comparison ofthe efficacy ofnicardipine, a new calcium channel blocker, with nifedipine in the treatment ofmild to moderate essential hypertension

C. Armstrong, J. Garnham and R. Blackwood Wexham Park Hospital, Slough and Chiltern International Limited, UK.

Summary: Thirty-nine patients with mild to moderate essential hypertension participated in a parallel, single-blind study comparing 6 weeks' treatment of nicardipine hydrochloride (90 mg/day) with nifedipine (40 mg/day). Nicardipine-treated patients commenced therapy with a significantly higher mean supine diastolic blood pressure than the nifedipine-treated patients. There was a statistically significant fall in blood pressure (systolic and diastolic) on both treatments at the 3 and 6 week follow-up visits. On adjusting the results for the baseline inequality, no statistically significant differences were found between treatment groups. Seven patients withdrew from nifedipine therapy and six patients withdrew from nicardipine therapy due to adverse events. The results show that nicardipine hydrochloride at 90 mg/day is an effective anti-hypertensive agent. The incidence and nature of adverse events were similar on the two treatments. copyright. Introduction The range of anti-hypertensive agents is wide. if they are clinically different in terms of efficacy and Diuretics or beta-blockers are being challenged as safety. first-line therapy in the treatment of mild to moderate essential hypertension. Calcium channel blockers have recently been advocated as possible first-line therapy. Materials and methods The main mechanism of action of calcium channel http://pmj.bmj.com/ blockers in hypertensive patients is to dilate arterioles Forty-one patients with mild to moderate essential and thus decrease peripheral vascular resistance.1'2'3 hypertension were assessed during a treatment-free, 2 Nicardipine hydrochloride is a new calcium channel week baseline period. Two patients were withdrawn blocker which is chemically related to nifedipine. It has during the treatment-free period and 39 patients been shown to be an effective anti-hypertensive agent48 entered a parallel, single-blind study and were ran- both in the short and long term. Nifedipine has also domly allocated to receive 6 weeks' treatment with been shown to be an effective anti-hypertensive either nicardipine hydrochloride (30 mg capsule three on September 27, 2021 by guest. Protected agent.9'4 Both calcium channel blockers act to times a day) or nifedipine (20 mg tablet twice daily). decrease peripheral vascular resistance thereby reduc- For inclusion in the study, patients were required to ing raised blood pressure. They also have other have supine diastolic blood pressure (phase V) bet- mechanisms of action. It has been shown that ween 95 and 125mm Hg. Patients with congestive nifedipine and nicardipine both have a resetting effect cardiac failure, cardiac dysrhythmias, history of on the baroreflex control mechanism.5",6 Nicardipine myocardial infarction or stroke in the 6 months prior has also been shown to have diuretic' and natriuretic to the study, grade 3 or 4 retinal hypertensive changes effects,'7 perhaps due to increased renal blood flow. or who needed urgent reduction of blood pressure This study was carried out to compare the two were excluded from the study, as were patients who structurally similar calcium channel blockers, nicar- had any serious mental or physical illness (including dipine hydrochloride and nifedipine, and to determine insulin treated diabetes mellitus). Of the 39 patients who received study medication, Correspondence: C.B. Armstrong, M.B., B.S. Wexham Park 13 patients withdrew due to adverse reactions. Data Hospital, Slough, Berks. SL2 4HL, UK. for these patients are included in the efficacy analyses Accepted: 27 November 1986 when available. Two patients did not take the study ©) The Fellowship of Postgraduate Medicine, 1987 Postgrad Med J: first published as 10.1136/pgmj.63.740.463 on 1 June 1987. Downloaded from

464 C. ARMSTRONG et al.

medication as instructed and two patients had dias- pressure and pulse rate were analysed at each assess- tolic blood pressures lower than 95 mm Hg on entry to ment using a one way ANOVA. Analysis of the study. These four patients were excluded from all covariance was used to deal with the problem of efficacy analyses. Thus, 28 patients, 18 male and 10 baseline differences between groups in supine diastolic female with a median age of 55 years (range 35-68), blood pressure. were included in the efficacy analyses. Fifteen patients Comparisons between baseline and follow-up received nifedipine and 13 patients received nicar- values for ECG and laboratory tests were made using dipine. Two patients in the nicardipine group and one Wilcoxon's signed rank test (within treatment groups) in the nifedipine group were untreated for hyperten- and Wilcoxon's rank sum test (between treatment sion in the 2 months prior to the study. All patients groups). In addition, the proportion of laboratory gave informed consent and approval for the study was results increasing/decreasing from baseline, those obtained from the hospital ethical committee. changing from normal to abnormal and vice versa; Blood pressure was measured in the right arm both and those with an increase or decrease from baseline of supine and standing using a random zero mercury more than 50% of the normal range were all analysed sphygmomanometer. The supine blood pressure was using a conditional binomial test. measured after the patient had rested for 2 minutes and the standing blood pressure was measured after the patient had been standing for 30 seconds. Weight Results was also recorded. Resting electrocardiograms, blood samples for haematology and biochemical analysis Bloodpressure and heart rate and urine for urinalysis were taken pre-study and at the end of the study. Table I shows the reductions in systolic and diastolic Adverse events were elicited by indirect questioning blood pressure after 3 and 6 weeks of treatment. All at each follow-up visit and compliance was checked by systolic and diastolic blood pressure reductions from a count of the returned medication. Based on the baseline for both treatment groups were statistically overall performance of each study medication as an significant (P< 0.05). At 6 weeks the mean diastolic copyright. effective and tolerable anti-hypertensive (global assess- blood pressure was reduced by 23.1 mm Hg for the ment), each treatment was graded as excellent, very nicardipine treatment group and 13.5mm Hg for the good, good, fair or poor. nifedipine treatment group. However, patients assigned to the nicardipine treatment group had statis- Statistical analysis tically significantly higher mean supine diastolic blood pressure at baseline than patients assigned to the The two groups were assessed for baseline com- nifedipine treatment group. On adjusting the results parability of demographic variables using Wilcoxon's for the baseline inequality no statistically significant http://pmj.bmj.com/ rank sum test and Fisher's exact test. Efficacy varia- differences were found between the two treatment bles at baseline were compared using one-way analysis groups. of variance (ANOVA). Changes from baseline blood Several patients withdrew from both groups during

Table I Supine and standing mean systolic and diastolic blood pressures (mm Hg)

Change from baseline at: on September 27, 2021 by guest. Protected Baseline Week 3 Week 6 Endpoint * Nicardipine Nifedipine Nicardipine Nifedipine Nicardipine Nifedipine Nicardipine Nifedipine Supine Systolic 187.4 183.7 -23.9 -14.5 -33.1 -15.6 -29.7 -15.7 (± s.d.) (23.9) (24.8) (21.8) (19.7) (22.7) (23.3) (23.6) (21.6) Diastolic 113.5 104.6t -17.8 -8.9 -23.1 -13.5 -21.2 -11.0 (± s.d.) (12.6) (7.6) (14.0) (10.0) (14.5) (15.5) (14.5) (14.9) Standing Systolic 164.6 168.7 - 19.7 - 19.6 -25.6 -24.0 -24.0 -23.4 (± s.d.) (15.7) (25.0) (13.6) (26.5) (13.0) (23.5) (13.4) (22.1) Diastolic 106.3 104.2 -16.1 -14.4 -20.5 -17.9 -20.6 -17.4 (± s.d.) (14.8) (8.8) (17.4) (15.2) (17.7) (13.2) (16.2) (12.1) * Endpoint = last available value for each patient t P < 0.05 two sample t test for equality of means. Postgrad Med J: first published as 10.1136/pgmj.63.740.463 on 1 June 1987. Downloaded from

NICARDIPINE AND NIFEDIPINE IN ESSENTIAL HYPERTENSION 465

active treatment. Analyses ofeach patient's last availa- diographic evidence of myocardial ischaemia at rest ble blood pressure values ('end point') were performed and the nifedipine-treated patient had left ventricular and the results are shown in Table I. hypertrophy at baseline which was not detected after 6 The clinical aim in this study was to reduce supine weeks' treatment. diastolic blood pressure to between 70 and 95 mm Hg. Thirty three ofthe 39 patients in this study reported Ten of 19 patients (53%) in the nicardipine treatment adverse events. Eighteen of 21 patients receiving group and 7 of 18 patients (39%) in the nifedipine nicardipine and 15 of 18 patients receiving nifedipine treatment group met this criterion by the end of complained of one or more adverse experiences. Six treatment. patients withdrew from nicardipine therapy and seven Supine heart rate was increased after both 3 and 6 patients withdrew from nifedipine therapy due to weeks of nicardipine treatment by means of 5 and 7 adverse events which resolved on cessation oftherapy. beats/minute respectively. The small increase after Most of the complaints were of a similar nature for nifedipine treatment (1 to 2 beats/minute) was not both treatment groups and appeared to be due to the statistically significant. There was no statistically vasodilatory effects of the drugs, e.g. headache, significant difference between treatments. oedema and flushing. When the change in diastolic blood pressure from supine to standing was compared between treatments, no statistically significant difference was found. Four Discussion patients in the nicardipine treatment group and three patients in the nifedipine group had diastolic blood Although nifedipine is widely used for hypertension pressure decreases of greater than 15 mm Hg on and often successfully, there is always a need for an standing, but had no symptomatic complaint suggest- alternative calcium antagonist particularly as up to ing clinically significant postural hypotension. The 20% of patients may be unable to tolerate it. Neither difference between treatments in change from baseline verapamil or diltiazem would be regarded as was 14.0 for supine systolic blood pressure and 3.46 for immediate alternatives to nifedipine."8 diastolic adjusted blood pressure. The chances ofthese The main mechanism by which blood pressure is copyright. results being statistically significant, given the small lowered by nifedipine and nicardipine is by a sig- number of patients, were 32% and 15% respectively. nificant reduction in total peripheral vascular resistance. Both nifedipine and nicardipine have a Other observations predominant effect on the peripheral vasculature. Neither calcium channel blocker causes any significant No clinically significant changes for laboratory tests electro-physiological effect on the heart. No studies were observed. The median change from baseline have so far compared the anti-hypertensive safety and

produced one statistically significant result which was efficacy of the new calcium channel blocker, nicar- http://pmj.bmj.com/ a median increase of 0.8 mmol/l in urea for nicardipine, with the established calcium channel blocker, dipine-treated patients. There were no statistically nifedipine. significant differences between treatments for any of This study has shown both drugs to reduce blood the laboratory tests. pressure significantly in patients with hypertension. At the end of the study, a mean decrease in The baseline inequality ofthe diastolic blood pressures bodyweight of 1.4kg in the nicardipine treatment in the two treatment groups makes it difficult to group and a mean increase of 0.4 kg in the nifedipine compare the absolute diastolic blood pressures. The treatment group were seen. The difference between acute response to nifedipine has been shown to be on September 27, 2021 by guest. Protected treatments was statistically significant (P < 0.05) but related to the pre-treatment blood pressure,9 i.e., the of doubtful clinical importance. higher the starting blood pressure the greater the Resting electrocardiograms were performed both decrease in blood pressure after nifedipine treatment, before and after treatment on 12 nicardipine-treated but this evidence has been challenged recently by a patients and 9 nifedipine-treated patients. There were report20 which showed that positive correlations are no statistically significant changes or differences mathematically inevitable. When statistical correction between treatments for PR and QRS intervals and was applied the correlation between the pre-treatment QTc. value and its change was no longer valid. In this study One nicardipine patient and one nifedipine patient nicardipine patients had a significantly higher mean showed new abnormalities on their electrocar- baseline diastolic blood pressure than the nifedipine diograms suggestive of worsening myocardial patients and the decrease in diastolic blood pressure ischaemia. Electrocardiograms for three patients, two was larger for patients on nicardipine than nifedipine. nicardipine-treated and one nifedipine-treated, When the diastolic blood pressure was adjusted for the showed improvements after 6 weeks of treatment. The baseline difference, no significant difference between two nicardipine-treated patients had less electrocar- treatments was found. Postgrad Med J: first published as 10.1136/pgmj.63.740.463 on 1 June 1987. Downloaded from

466 C. ARMSTRONG et al.

This study also looked for any postural hypotension symptoms resolved on cessation of treatment. The effects of the two drugs. Postural hypotension has majority ofthe symptoms reported appeared to be due been reported in one study with nifedipine,'0 although to the vasodilator properties of these drugs, e.g. other studies examining the effects of nicardipine7 and flushing, headache and oedema. Two patients taking nifedipine'4 have found no postural hypotensive nicardipine and three taking nifedipine reported effects of either drug. In this study there was no oedema. However, on examining weight changes, significant difference between the two drugs for there was only a marginal increase in weight for change in blood pressure on standing. Patients having patients receiving nifedipine and a decrease in weight a significant decrease in blood pressure on standing for patients receiving nicardipine. Oedema is probably reported no symptoms of postural hypotension. due to fluid redistribution following local vasodilata- A large proportion ofpatients reported one or more tion. The small mean weight decrease seen in nicar- adverse experiences. Most of these experiences were dipine-treated patients may be due to its mild diuretic transient and were tolerated by the patients. Seven effect.2' patients in the nifedipine treatment group and six This study has shown that nicardipine can be used patients in the nicardipine treatment group withdrew successfully as monotherapy in the treatment of mild because of adverse experiences. Twelve of the 13 to moderate hypertension. Both nicardipine and patients who withdrew for adverse experiences did so nifedipine were shown to be safe and effective anti- within the first 3 weeks of the study. All these hypertensive agents.

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